Abstract Proteostasis is essential for cell health and viability, and involves complex and highly conserved networks that regulate protein translation, protein folding, and protein degradation. A decline in proteostasis function is one of the features of aging tissues, particularly of the central nervous system (CNS). Indeed, the aging brain is particularly sensitive to proteotoxic stress, as demonstrated by the high number of age-associated neurodegenerative disorders characterized by protein misfolding and aggregation, including Alzheimer's disease (AD). The regulation of non-cell autonomous proteostasis has recently arisen as a novel mechanism for the modulation of systemic homeostasis in worms and flies, and is postulated to have important organismal effects on metabolism and aging. However, to date, there are no studies addressing the existence and activity of these pathways in mammals, and their potential effects on the aging brain. Transcription Factor E-B (TFEB) is a powerful master transcription factor regulator of proteostasis, integrating autophagy and bioenergetics. We recently derived transgenic mice that moderately over- express TFEB in skeletal muscle, and discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity in the CNS and also improve cognition and memory in aging mice. In this project, we will determine if enhanced skeletal muscle proteostasis is capable of promoting neuroprotection, uncover the mechanistic basis for this effect, develop powerful new models for testing mitophagy/autophagy activity in the aging CNS, and determine if soluble factors secreted by muscle (?myokines?) mediate the beneficial CNS effects in conditional skeletal muscle- expressing TFEB transgenic mice. Identification of pathways regulating cross-talk between skeletal muscle and CNS may yield targets with high therapeutic potential for diseases of the aging CNS.